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WO2011025271A2 - Ascorbate de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combiné le comprenant - Google Patents

Ascorbate de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combiné le comprenant Download PDF

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Publication number
WO2011025271A2
WO2011025271A2 PCT/KR2010/005714 KR2010005714W WO2011025271A2 WO 2011025271 A2 WO2011025271 A2 WO 2011025271A2 KR 2010005714 W KR2010005714 W KR 2010005714W WO 2011025271 A2 WO2011025271 A2 WO 2011025271A2
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metformin
cancer
ascorbate
composition
diabetes
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WO2011025271A3 (fr
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김성욱
전성수
민창희
구자성
강민석
김용은
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Hanall Biopharma Co Ltd
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Hanall Biopharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/62—Three oxygen atoms, e.g. ascorbic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a novel salt of metformin, a method for preparing the same, a pharmaceutical composition comprising the same, and a combination formulation comprising the same.
  • N, N-dimethyl imidodicarbonimidic diamide (N, N-dimethyl imidodicarbonimidic diamide) is commonly known as metformin, which is an insulin-independent diabetes treatment drug. Is a biguanide-based drug that has the best hypoglycemic action and is most effective in preventing complications and worsening of symptoms.
  • metformin is the only drug of choice.
  • metformin's efficacy activates AMP-activated protein kinase (AMPK) has justified its clinical effectiveness.
  • AMPK is a key enzyme that physiologically regulates carbohydrate metabolism and lipid metabolism. Metformin activates this enzyme to normalize hyperglycemia, improve lipid status, normalize menstrual irregularities, ovulation and pregnancy, and treat fatty liver and gene p53 (Tumor). protein p53) has been reported to prevent and treat cancer.
  • metformin an AMPK enzyme activator, was effective in the prevention and treatment of cancers lacking the p53 gene [Monica Buzzai, et al. Syntemic Treatment with the Antidiabetic Drug Metformin Selectively Impairs p53-Deficient Tumor Cell Growth, Cancer Res 2007; 67: (14). July 15, 2007].
  • metformin is a drug that normalizes sugar and lipid metabolism by activating the AMPK enzyme.
  • metformin is administered to cancers lacking the p53 gene, the energy metabolic pathways of cancer cells are changed and anticancer activity increases in proportion to the dose of metformin. Metformin has been shown to be effective in treating cancer at normal doses for treating diabetes.
  • Josie MM Evans published a study showing that the incidence of cancer in patients with type 2 diabetes is lower than those who do not receive metformin [Josie MM, Evans et al. BMJ. 2005 , 330, 1304-1305], Samantha L. Bowker reported that patients with type 2 diabetes who take metformin have a lower mortality rate associated with cancer than patients who take sulfonylureas or take insulin [Samantha L et al. Diabetes Care. 2006, 29, 254-258.
  • metformin is useful in the free base form, but it is administered in the form of a pharmaceutically acceptable acid addition salt because of the disadvantage of poor stability.
  • metformin is sold in the form of hydrochloride, and other metformin salts are metformin folate in Chinese Patent Publication No. CN 1962661A, metformin 1,2,6,7,8,8a-hexahydro- in WO 2005/033067.
  • Beta gamma, 6-trihydroxy-2-methyl-8-[(2s) -2-methyl-1-oxobutoxy]-, (betaR, gammaR, 1S, 2S, 6S, 8S, 8aS) -1-naphthaleneheptarate, metformin acetylsalicylate in US Pat. No. 3,957,853, metformin clofibrate salt in US Pat. No.
  • vitamin C as one of the water-soluble vitamins, and the development and sale of health drinks and functional foods is continuously expanding as a safe substance with little reported toxicity.
  • One technical problem to be solved by the present invention is to provide a metformin novel salt excellent in pharmacological effect.
  • Another technical problem to be solved by the present invention is to provide a method for producing a metformin novel salt.
  • Another technical problem to be solved by the present invention is diabetes, diabetes, metabolic syndrome, diabetes complications, menstrual irregularities, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome
  • a pharmaceutical composition for preventing, alleviating or treating a disease or condition selected from cancer, myalgia, myococytosis, rhabdomyolysis, or menopausal syndrome is provided.
  • Another technical problem to be solved by the present invention is to provide an antioxidant pharmaceutical composition comprising a metformin novel salt as an active ingredient.
  • Another technical problem to be solved by the present invention is to provide a combination formulation comprising a metformin novel salt and a second drug.
  • the present invention provides metformin ascorbate.
  • the binding molar ratio of metformin and ascorbate is preferably from 2: 1 to 1: 2, and more preferably from 1: 1 molar ratio of metformin ascorbate of formula (1).
  • metformin ascorbate is meant to include all anhydrides, hydrates (hemihydrates, monohydrates, dihydrates, trihydrates, and the like) of metformin ascorbate, solvates and the like.
  • the metformin ascorbate may also be in crystalline form.
  • the present invention comprises the steps of 1) reacting the metformin hydrochloride with an inorganic base to obtain a metformin free base; And 2) reacting the metformin free base obtained in step 1 with ascorbic acid to produce metformin ascorbate.
  • metformin hydrochloride used as starting material can be purchased commercially or prepared by a known method.
  • the inorganic base of step 1 means a conventional inorganic base used in the field of organic chemical manufacturing, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, Sodium hydrogen carbonate, or potassium hydrogen carbonate, but examples thereof are not limited to the inorganic base that can be used in the present invention.
  • the use equivalent weight of the inorganic base is preferably 0.7 to 4 molar equivalents, more preferably 0.9 to 4 molar equivalents, and even more preferably 0.9 to 1.5 molar equivalents, relative to 1 molar equivalent of metformin hydrochloride. .
  • the reaction temperature is preferably 0 to 60 ° C, more preferably 15 to 50 ° C.
  • the reaction time is preferably 30 minutes to 3 hours, but may vary depending on the reaction temperature.
  • ascorbic acid may be purchased and used commercially.
  • the ascorbic acid use equivalent is preferably 0.7 to 4 molar equivalents, more preferably 0.9 to 4 molar equivalents, more than 0.9 to 1.5 molar equivalents, relative to 1 molar equivalent of metformin free base. desirable.
  • the reaction temperature is preferably 0 to 80 °C, the reaction temperature may vary depending on the type of reaction solvent.
  • the reaction solvent is water, it is preferable to react at room temperature (15 to 30 °C), and in the case of isopropanol, it is preferred to react by heating to 50 to 60 °C.
  • the reaction solvent is water or methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, pentanol, acetone, dioxane, dimethylformamide, dimethyl sulfoxide, acetonitrile, tetra
  • methanol is preferred in step 1 and water or isopropanol is preferred in step 2.
  • metformin ascorbate represented by Chemical Formula 1 may be prepared by the steps represented by Schemes 1 and 2.
  • the present invention is diabetes, diabetes, metabolic syndrome, diabetes complications, dysmenorrhea, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity, containing metformin ascorbate as an active ingredient
  • a pharmaceutical composition for the prevention, alleviation or treatment of one or more diseases or symptoms selected from symptom and rhabdomyolysis, or menopausal syndrome may be due to the activating action of AMPK ⁇ .
  • it may be for simultaneously preventing, alleviating or treating cancer and diabetes.
  • the cancer may be a cancer lacking the p53 gene.
  • the cancer may be cancer selected from the group consisting of uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, colon cancer, lung cancer, skin cancer, blood cancer, liver cancer, pancreatic cancer, prostate cancer and thyroid cancer, preferably lung cancer Can be.
  • diabetes includes not only diabetes but also diabetes of those with metabolic syndrome, which means that diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis or polycystic ovary syndrome are combined.
  • metabolic syndrome means that diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis or polycystic ovary syndrome are combined.
  • the complications of diabetes are the same as the disease or condition referred to as metabolic syndrome.
  • composition may be for the prevention, alleviation or treatment of cancer.
  • the composition of the present invention may be for co-administration with a second drug.
  • the second drug means another pharmaceutically effective ingredient other than metformin ascorbate of the present invention.
  • the metformin ascorbate of the present invention can be used for the treatment of various diseases as described above.
  • the metformin ascorbate of the present invention can be used in combination with a second drug for more efficient treatment of each disease.
  • the second drug may be an anticancer agent, an antihyperglycemic agent, an antiobesity agent, or the like.
  • the antihyperglycemic agent may be for prevention, alleviation or treatment of diabetes mellitus, diabetes, metabolic syndrome, and / or diabetes complications due to hyperglycemia, and the antiobesity agent may be for prevention, alleviation or treatment of obesity.
  • the antihyperglycemic agent may be at least one drug selected from the group consisting of biguanide-based drugs, sulfonylurea-based drugs, thiazolidione-based drugs, and alpha-glocosidase inhibitors.
  • the anticancer agent is not limited as long as it can be used in combination with metformin ascorbate, but may be a biological agent such as a gene therapy agent in addition to known chemotherapeutic agents such as alkylating agents, metabolic antagonists, natural agents, hormones, and / or antagonists, and / or immunotherapy agents. Can be.
  • the antihyperglycemic agent is not limited as long as it can be used in combination with metformin ascorbate, but is not limited to acarbose, miglitol, bogliose, pramlinted, buformin, metformin, phenformin, allogliptin, sasagliptin, cytagliptin , Stammagliptin, Exenatide, Reroglutide, Insulin, Mytiglinide, Nateglinide, Repaglinide, Setohexamide, Carbutamide, Chlorpropamide, Glibenclamide, Glyborneuride, Glyclagit, glymepiride, glyphigit, glyquidone, glycentide, glysolamide, glycyclamide, tol azamide, tolbutamide, pioglitazone, rosiglitazone, and / or troglitazone.
  • the anti-obesity agent is not limited if it can be used in combination with metformin ascorbate, but not limited to dexamphetamine, caffeine, dexfenfluramine, diethylpropion, ephedrine, fenfluramine, fluoxetine, leptin, liraglutide, magdol, metformin, methylcellulose, oligo Start, penmetrazine, phentermine, phenylpropanolamine, limonabant, sibutramine, stuculia, sucrose, polyester, tefenfencin, topiramate, and / or zonamide.
  • the present invention also provides an antioxidant pharmaceutical composition containing metformin ascorbate as an active ingredient.
  • the antioxidant may be due to the activating action of AMPK ⁇ .
  • the antioxidant may prevent, alleviate and / or treat cancer, aging, heart disease, brain disease, arteriosclerosis, inflammation, and / or immune diseases.
  • prevention means any action that inhibits or delays the onset of a disease or condition by administration of a composition of the present invention.
  • treatment means any action that improves or beneficially changes the symptoms of the disease by administration of the composition of the present invention
  • laxation means that the disease or symptom is no longer worsened by administration of the composition of the present invention. It means all actions.
  • compositions of the present invention may be in the form of conventional formulations that are acceptable and commonly used in the medical arts and may be, for example, tablets, soft capsules, hard capsules, pills, granules, powders, injections or solutions.
  • the composition may be selected from sustained or immediate release.
  • the sustained release means that the release of the active ingredient occurs slowly, including the base used for the purpose of sustained release in addition to the active ingredient, the immediate release means that the active ingredient is released immediately.
  • the tablet may be a sustained release tablet or an immediate release tablet.
  • compositions of the present invention may further comprise a pharmaceutically acceptable carrier, diluent or excipient.
  • a component selected from an enteric polymer, a hydrophobic substance, a hydrophilic polymer, and the like may be used as the matrix base used for sustained release.
  • the enteric polymer include polyvinylacetate phthalate, hydroxypropylmethyl cellulose phthalate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, poly (methacrylic acid and methyl methacrylate) copolymer, and poly (methacrylic acid, ethylacrylic). Rate) copolymers and the like can be used one or more, preferably hydroxypropyl methyl cellulose phthalate is used.
  • the hydrophobic materials are pharmaceutically acceptable polyvinyl acetate, poly (methacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate as polymethacrylate copolymers).
  • Acrylates copolymers, ethyl cellulose and cellulose acetate, fatty acids and fatty acid esters, fatty alcohols, waxes and inorganic substances, and the like, specifically, glyceryl palmitostearate, Fatty acid alcohols such as glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and stearic acid, such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol, as waxes, carnauba wax, beeswax Talc, sedimentation as an inorganic material, such as microcrystalline wax Selecting an acid, calcium hydrogen phosphate, calcium oxide, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and one or two or more selected from such bigeom and the like can be used.
  • glyceryl palmitostearate Fatty acid alcohols such as glyceryl stearate, glyceryl
  • the hydrophilic polymer may be selected from sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives and carboxyvinyl polymers, and specifically, as the sugars, dextrin, polydextrin, dextran, Pectin and pectin derivatives, alginates, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose, amylopectin and the like can be selected and used as cellulose derivatives.
  • Hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose and the like can be selected and used as a gum , Locker Soybean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, xanthan gum, etc. can be selected and used, and gelatin, casein, zein, etc.
  • polyvinyl derivatives as polyvinyl derivatives Alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylamino acetate, and the like can be selected and used as the polymethacrylate copolymer, and poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate Rate) copolymer, etc. can be selected and used, polyethylene glycol, polyethylene oxide, etc. can be selected and used as a polyethylene derivative, and a carbomer can be used as a carboxyvinyl polymer.
  • Starch microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol and / or dicalcium phosphate may be used as a pharmaceutically acceptable diluent without impairing the effects of the present invention. have.
  • starch starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone and / or gelatin, etc. Can be used.
  • Starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch as a disintegrating agent, clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or carboxy Celluloses such as methyl cellulose, algins such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, gums such as guar gum and xanthan gum, and crosslinks such as crospovidone A polymer and boiling agents, such as sodium bicarbonate and a citric acid, can be selected and used.
  • clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or carboxy Celluloses such as methyl cellulose, algins such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, gums such as guar gum and
  • Lubricants include talc, magnesium stearate and alkaline earth metal stearate type calcium, zinc, lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, polyethylene glycol 4000 and / or polyethylene glycol 6000 Etc. can be used.
  • metformin ascorbate can be utilized as a preparation for oral administration in various forms.
  • the dosage is preferably from 50 to 3,000 mg of metformin ascorbate (based on metformin free base), but may vary depending on the age, sex, weight, nationality, health condition and degree of disease of the patient. Depending on the judgment, divided doses may be given once or twice a day.
  • the present invention is metformin ascorbate diabetes mellitus, diabetes mellitus, metabolic syndrome, diabetes complications, menstrual irregularities, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity, rhabdomyolysis or Provided are one or more disease prophylactic, symptomatic or therapeutic uses selected from menopausal syndrome.
  • the present invention is an effective amount of metformin ascorbate diabetes mellitus, diabetes mellitus, metabolic syndrome, diabetes complications, menstrual disorders, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity, rhabdomyolysis Or administering to a mammal comprising a human in need of preventing, alleviating or treating one or more diseases selected from menopausal syndrome.
  • the present invention also provides an antioxidant method comprising administering to a mammal, including a human, in need of an effective amount of metformin ascorbate.
  • cancer By the antioxidant method, cancer, aging, heart disease, brain disease, arteriosclerosis, inflammation, and / or immune diseases can be prevented or treated.
  • the term “administration” means introducing the metformin ascorbate and / or pharmaceutical composition of the invention to a patient in any suitable manner, wherein the route of administration of the metformin ascorbate and / or pharmaceutical composition of the invention is intended for Administration can be by any general route as long as it can be reached.
  • the present invention is selected from diabetes, diabetes mellitus, metabolic syndrome, diabetes complications, menstrual irregularities, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, myococytosis, rhabdomyolysis or menopausal syndrome Metformin ascorbate is provided for the prevention, alleviation or treatment of one or more diseases or conditions.
  • the present invention also provides metformin ascorbate for antioxidant.
  • the present invention also provides a pharmaceutical formulation comprising the metformin ascorbate of the present invention and a second drug.
  • the active ingredient in the composition or formulation of the present invention may be included in 10 to 95% by weight based on the total weight.
  • the metformin ascorbate and the composition of the present invention exhibits excellent AMPK ⁇ activating action, such as diabetes, diabetes, metabolic syndrome, diabetic complications, menstrual irregularities, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia It is effective in the treatment or prophylaxis of muscle cell toxicity, rhabdomyolysis and / or menopausal syndrome and has an antioxidant effect.
  • metformin ascorbate of the present invention provides a crystalline acid addition salt suitable for the preparation of pharmaceutical formulations, which is low toxicity by using ascorbate having a relatively low toxicity compared to conventional metformin hydrochloride prepared using hydrochloric acid. It has the effect of increasing the pharmaceutical and physical advantages such as solubility, stability, non-hygroscopicity and ease of processing of tablet formulations.
  • metformin ascorbate can be easily produced by the production method of the present invention.
  • the co-formulation of the present invention is excellent in pharmacological effects and can promote the convenience of the patient's medication.
  • Figure 1 shows the IR spectrum for metformin ascorbate in accordance with one embodiment of the present invention.
  • FIG. 2 is a graph confirming the activation effect of AMPK ⁇ of metformin ascorbate according to an embodiment of the present invention.
  • the reagents and solvents mentioned below were purchased from Aldrich, USA and Daejin, Korea.
  • the 1 H-NMR and 13 C-NMR data are measured by Innova 600 MHz FT-NMR from Verian, USA, and the melting point (mp) is No. 1 of Electrothermal, UK.
  • Metformin ascorbate is a crystalline acid addition salt that is suitable for the manufacture of pharmaceutical formulations, so that ascorbate, which is relatively less toxic than conventional metformin hydrochloride prepared using hydrochloric acid, is not only toxic but also has solubility, stability, non-hygroscopicity and It has the effect of increasing the pharmaceutical and physical advantages such as ease of processing of tablet formulations.
  • the final mixture was compressed into tablets containing 380.8 mg of metformin ascorbate in one tablet.Opadry O3B28796 (hydroxypropylmethylcellulose 62.50%, titanium oxide) using a high coater (SFC-30N, Sejong Machinery, Korea) 31.25%, polyethylene glycol 400 6.25%; Colorcon; USA) as a coating base to form a film coating layer of 15mg per tablet to prepare a tablet containing metformin ascorbate.
  • a high coater SFC-30N, Sejong Machinery, Korea
  • the final mixture was then compressed into tablets containing 921.63 mg of metformin ascorbate in one tablet.
  • the final mixture was compressed to prepare a sustained-release tablet containing 380.8 mg of metformin ascorbate in one tablet, and as a high coater (SFC-30N, Sejong Machinery, Korea), Opadry O3B28796 as a coating base, 15 mg film per tablet.
  • the coating layer was formed to produce a sustained release metformin tablet containing metformin ascorbate.
  • the final mixture was compressed to prepare a sustained-release tablet containing 380.8 mg of metformin ascorbate in one tablet, and a high coater (SFC-30N, Sejong Machinery, Korea) was coated with Opadry O3B28796 as a coating base.
  • the coating layer was formed to produce a sustained release metformin tablet containing metformin ascorbate.
  • the final mixture was compressed to prepare a sustained-release tablet containing 380.8 mg of metformin ascorbate in one tablet, and a high coater (SFC-30N, Sejong Machinery, Korea) was coated with Opadry O3B28796 as a coating base.
  • the coating layer was formed to produce a sustained release metformin tablet containing metformin ascorbate.
  • the final mixture was compressed into tablets containing 460.8 mg of metformin ascorbate and 150 mg of capecitabine in one tablet, and coated with Opadry O3B28796 as a high coater (SFC-30N, Sejong Machinery, Korea).
  • Opadry O3B28796 as a high coater (SFC-30N, Sejong Machinery, Korea).
  • a film coating layer of 15 mg per tablet was formed to prepare a film-coated tablet containing metformin ascorbate and capecitabine.
  • Metformin ascorbate synthesized in the manner described in Example 1 of the present invention was treated with cancer cells to determine the effect of inhibiting cancer cell proliferation.
  • the experimental method is as follows.
  • MTT (3- (4,5-dimethylthiazole-2-yl) -2,5-ditetrazoliumbromide) assay was used to determine the percentage of cell survival rate of metformin ascorbate. The cancer cell proliferation inhibitory effect was confirmed.
  • A549 cell line (Korea Cell Line Bank) was incubated for 24 hours in a 96 well plate so that each cell number was approximately 5000 in DMEM (Dulbecco's modified Eagle's medium) containing 10% calf serum. Thereafter, 2mM and 10mM of metformin ascorbate, synthesized in the manner described in Example 1, were treated in the culture solution and cultured for 72 hours. In addition, in order to obtain GIC 50, metformin ascorbate 10 mM, 2 mM, 0.4 mM, 0.08 mM, 0.016 mM were respectively treated in the culture solution and incubated for 72 hours.
  • MTT was added to the culture to incubate for 3 hours further to confirm viable cells after metformin ascorbate treatment.
  • the resulting formazan crystal was dissolved using dimethyl sulfoxide (DMSO), and then the absorbance of the solution was measured at 560 nm.
  • DMSO dimethyl sulfoxide
  • the number of cells surviving in the well plate treated with metformin ascorbate compared to the number of cells cultured in the well plate not treated with metformin ascorbate was expressed as cell viability (%).
  • the concentration of metformin ascorbate (GIC 50) in which growth was inhibited to 50% using a cell viability curve was calculated to confirm the effect of inhibiting cancer cell proliferation of metformin ascorbate, and the results are shown in Table 1 and Table 2, respectively. It was.
  • metformin hydrochloride or ascorbic acid was used instead of metformin ascorbate to obtain cell viability (%) and GIC 50 values, and the results are shown in Tables 1 and 2, respectively.
  • metformin ascorbate could inhibit the growth of A549 cells by 50%, whereas metformin hydrochloride had to be treated with 3.5 mM to increase the cell growth by 50%. could be restrained. Therefore, it was found that the use of metformin ascorbate in a smaller amount than metformin hydrochloride can effectively inhibit the growth of cancer cells, especially cancer cells derived from lung cancer.
  • the effect of activating AMPK ⁇ was measured by treating cells with metformin ascorbate synthesized in the manner described in Example 1 of the present invention.
  • the experimental method is as follows.
  • AMPK ⁇ (5′-AMP-activated protein kinase alpha) activation of metformin ascorbate was confirmed in MCF 7 cell line (Korea Cell Line Bank) derived from human breast cancer cells using AMPK ⁇ immunoassay kit (Invitrogen, catalog No. KHO0651). It was.
  • the MCF 7 cell line (Korea Cell Line Bank) was cultured in DMEM medium containing 10% calf serum, placed in a 6-well plate so that the number of cells was about 5 ⁇ 10 5 , and then incubated with 5% CO 2. Cells were cultured. The culture solution was treated with 2 mM metformin ascorbate, and then cultured for 24 hours.
  • threonine 172 residue (T172) of AMPK ⁇ in cells cultured in the presence of metformin ascorbate and cells cultured without metformin ascorbate was confirmed using an AMPK ⁇ immunoassay kit (Invitrogen, catalog No. KHO0651). After lysing the cells in the manner suggested by the AMPK ⁇ immunoassay kit (Invitrogen, catalog No. KHO0651), the method was described in the instructions for use of the AMPK ⁇ immunoassay kit. The degree of phosphorylation of threonine 172 residue of AMPK ⁇ from the cell lysate was used and the results are shown in Table 3 and FIG. 2. The ratio of the degree of phosphorylation of cells cultured in the presence of metformin ascorbate to the degree of phosphorylation of cells cultured in medium without metformin ascorbate is shown in Table 3.
  • metformin ascorbate effectively activates AMPK ⁇ . Accordingly, metformin ascorbate may be used to treat diabetes, diabetes, metabolic syndrome, diabetic complications, menstrual irregularities, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, myococytosis, rhabdomyolysis, and It can be seen that it may have an excellent effect on diseases such as menopausal syndrome.
  • the present invention provides metformin ascorbate, a preparation method thereof, a pharmaceutical composition comprising the same, and a combination formulation comprising the same.
  • Metformin ascorbate of the present invention has excellent stability and ease of processing of tablets, low toxicity, diabetes, diabetes, metabolic syndrome, diabetes complications, menstrual irregularities, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, It is effective in cancer, myalgia, myococytosis, rhabdomyolysis, postmenopausal syndrome, and / or antioxidant, and thus has industrial applicability.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de l'ascorbate de metformine, un procédé de préparation correspondant, une composition pharmaceutique le comprenant et une formulation combinée le comprenant. L'ascorbate de metformine selon l'invention a une meilleure stabilité, il peut être facilement comprimé et il présente une faible toxicité, ce qui permet de l'utiliser efficacement pour traiter une glycosurie, un diabète, un syndrome métabolique, des complications du diabète, des irrégularités menstruelles, une hypertension, une hyperlipidémie, une stéatose hépatique, une coronaropathie, une ostéoporose, le syndrome des ovaires polykystiques, un cancer, une myalgie, des symptômes liés à la cytotoxicité dans la cellule musculaire, une rhabdomyolyse, un climactère, etc., et/ou il permet d'obtenir une activité anti-oxydante.
PCT/KR2010/005714 2009-08-25 2010-08-25 Ascorbate de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combiné le comprenant Ceased WO2011025271A2 (fr)

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US9139558B2 (en) 2007-10-17 2015-09-22 Wyeth Llc Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US9211264B2 (en) 2009-11-09 2015-12-15 Wyeth Llc Coated drug spheroids and uses thereof for eliminating or reducing conditions such as emesis and diarrhea
US9211291B2 (en) 2009-04-06 2015-12-15 Wyeth Llc Treatment regimen utilizing neratinib for breast cancer
US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US10596162B2 (en) 2005-02-03 2020-03-24 Wyeth Llc Method for treating gefitinib resistant cancer
US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272
CN112716949A (zh) * 2021-02-03 2021-04-30 天津科技大学 一类抗肿瘤药物组合物、制剂和应用
WO2022184981A1 (fr) 2021-03-03 2022-09-09 Orion Corporation Compositions pharmaceutiques stables de metformine
RU2813333C1 (ru) * 2022-11-23 2024-02-12 Федеральное Государственное бюджетное образовательное учреждение высшего образования Дагестанский государственный медицинский университет Министерства здравоохранения Российской Федерации Способ коррекции нарушений менструального цикла у женщин с метаболическим синдромом
US12031128B2 (en) 2021-04-07 2024-07-09 Battelle Memorial Institute Rapid design, build, test, and learn technologies for identifying and using non-viral carriers
US12109223B2 (en) 2020-12-03 2024-10-08 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
ES2990069A1 (es) * 2023-04-24 2024-11-28 Fundacion Univ San Antonio Ucam Combinacion sinergica para el tratamiento de cancer
US12441996B2 (en) 2023-12-08 2025-10-14 Battelle Memorial Institute Use of DNA origami nanostructures for molecular information based data storage systems
US12458606B2 (en) 2023-09-29 2025-11-04 Battelle Memorial Institute Polymer nanoparticle compositions for in vivo expression of polypeptides

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FR2796551B1 (fr) * 1999-07-23 2003-07-25 Lipha Nouveaux sels de metformine, leur procede d'obtention et les compositions pharmaceutiques en renfermant
US20030220301A1 (en) 2002-02-14 2003-11-27 Sonus Pharmaceuticals, Inc. Metformin salts of lipophilic acids
WO2005023766A1 (fr) * 2003-09-11 2005-03-17 Biocon Limited Sel d'atorvastatine associee a de la metformine

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US10596162B2 (en) 2005-02-03 2020-03-24 Wyeth Llc Method for treating gefitinib resistant cancer
US10603314B2 (en) 2005-02-03 2020-03-31 The General Hospital Corporation Method for treating gefitinib resistant cancer
US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272
US9630946B2 (en) 2007-10-17 2017-04-25 Wyeth Llc Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US9139558B2 (en) 2007-10-17 2015-09-22 Wyeth Llc Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US10035788B2 (en) 2007-10-17 2018-07-31 Wyeth Llc Maleate salts of (E)-N-{4[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US10111868B2 (en) 2008-06-17 2018-10-30 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US9211291B2 (en) 2009-04-06 2015-12-15 Wyeth Llc Treatment regimen utilizing neratinib for breast cancer
US9211264B2 (en) 2009-11-09 2015-12-15 Wyeth Llc Coated drug spheroids and uses thereof for eliminating or reducing conditions such as emesis and diarrhea
US12109223B2 (en) 2020-12-03 2024-10-08 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12433910B2 (en) 2020-12-03 2025-10-07 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
CN112716949A (zh) * 2021-02-03 2021-04-30 天津科技大学 一类抗肿瘤药物组合物、制剂和应用
WO2022184981A1 (fr) 2021-03-03 2022-09-09 Orion Corporation Compositions pharmaceutiques stables de metformine
US12031128B2 (en) 2021-04-07 2024-07-09 Battelle Memorial Institute Rapid design, build, test, and learn technologies for identifying and using non-viral carriers
RU2813333C1 (ru) * 2022-11-23 2024-02-12 Федеральное Государственное бюджетное образовательное учреждение высшего образования Дагестанский государственный медицинский университет Министерства здравоохранения Российской Федерации Способ коррекции нарушений менструального цикла у женщин с метаболическим синдромом
ES2990069A1 (es) * 2023-04-24 2024-11-28 Fundacion Univ San Antonio Ucam Combinacion sinergica para el tratamiento de cancer
US12458606B2 (en) 2023-09-29 2025-11-04 Battelle Memorial Institute Polymer nanoparticle compositions for in vivo expression of polypeptides
US12441996B2 (en) 2023-12-08 2025-10-14 Battelle Memorial Institute Use of DNA origami nanostructures for molecular information based data storage systems

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